Journal article
Biased Signaling Agonists Promote Distinct Phosphorylation and Conformational States of the Dopamine D3 Receptor
International journal of molecular sciences, v 25(19), p10470
28 Sep 2024
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Biased agonists of G-protein-coupled receptors (GPCRs) have emerged as promising selective modulators of signaling pathways by offering therapeutic advantages over unbiased agonists to minimize side effects. The dopamine D3 receptor (D3R), a pivotal GPCR in the central nervous system, has gained significant attention as a therapeutic target for neurological diseases, including Parkinson’s disease (PD), addiction, psychosis, depression, and anxiety. We have recently designed and tested SK609, a G-protein biased D3R selective agonist, and demonstrated its efficacy in reducing motor impairment and improving cognitive effects in a rodent model of PD. The molecular mechanism by which SK609 recruits G-protein but not β-arrestin pathways is poorly understood. Utilizing all-atom molecular dynamics simulations, we investigated the distinct conformational dynamics imparted by SK609 and the reference unbiased agonist Pramipexole (PRX). Results from these studies show that the flexibility of transmembrane 3 is key to unbiased signaling, with a ~30° and ~17° shift in tilt angle in the D3R-Gi and D3R-βarrestin2 complexes, respectively. Additionally, untargeted phosphoproteomics analysis reveals unique phosphorylation sites by SK609 and PRX in D3R. These results suggest that SK609 induces conformational changes and unique phosphorylation patterns that promote interactions with G-proteins and are not conducive for β-arrestin2 recruitment and signaling.
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Details
- Title
- Biased Signaling Agonists Promote Distinct Phosphorylation and Conformational States of the Dopamine D3 Receptor
- Creators
- Binod Nepal - Drexel UniversityJessica Barnett - Drexel UniversityFrank Bearoff - Drexel UniversitySandhya Kortagere - Drexel University
- Publication Details
- International journal of molecular sciences, v 25(19), p10470
- Publisher
- MDPI; BASEL
- Number of pages
- 21
- Grant note
- NIH-R44NS117201: NIH-R44NS117201, MCB210021P
This research work was supported partly by the NIH-R44NS117201. Anton2 supercomputer time was provided by the Pittsburgh Supercomputing Center through Grant MCB210021P.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:001334117300001
- Scopus ID
- 2-s2.0-85206450005
- Other Identifier
- 991021906079804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary